(1) Field of the Invention
The present invention relates to a dialysis agent A used as a two pack type dialysis agent containing acetic acid and acetate salt. More specifically, the present invention relates to a dialysis agent A used to prepare a bicarbonate dialysate together with a dialysis agent B containing sodium hydrogen carbonate, that can adjust the total acetate ion concentration in the dialysate to less than 6 mEq/L and is excellent in the storage stability of glucose and the like, as well as able to reduce the acetic acid odor and suppress the corrosion of the dialysate delivery system and the dialysis machine. Furthermore, the present invention relates to a two pack type dialysis agent containing the dialysis agent A.
(2) Description of Related Art
Dialysis therapy has been established as a treatment for patients with renal insufficiency, and performed for the purpose of controlling the concentration of blood electrolyte components, removal of uremic substances, correction of acid-base balance, or the like. Although a plurality of components are included in the dialysis solution used in the dialysis treatment, the components satisfying the objectives of treatment and with less burden on the living body should be combined at appropriate concentrations.
In recent years, a bicarbonate dialysate using sodium hydrogen carbonate for the correction of acid-base balance has become the mainstream in the hemodialysis solution, and it is also essential to combine an acid to make the dialysate neutral. Further, when these are distributed in the same container in which they coexist, such components generate carbon dioxide gas in the container, so that they become very unstable, because of which two agents separated into agent A and agent B as a dialysis agent used for the preparation of the dialysate are generally mixed at the time of use.
Usually, the agent A contains sodium chloride, potassium chloride, calcium chloride, magnesium chloride, pH adjusting agent (acid and buffer components as optional components), and glucose, and the agent B contains sodium hydrogen carbonate. Moreover, in order to prevent the precipitation of insoluble salts, it is said that the formulation of calcium chloride and magnesium chloride into the agent B is contraindicated.
Conventionally, these agents A and B have been used as a liquid filled in a polyethylene container, but transportation costs and poor workability in hospitals (weight, storage space, and disposal method of polyethylene container) have become a problem. As a result, today, a dialysis agent in powder form to be mixed with water before use has been put into practical use.
Although the dialysis agent in powder form was originally comprised of three agents including an agent A-1 containing a pH adjusting agent and an electrolyte, an A-2 agent consisting of only glucose, and an agent B consisting of sodium hydrogen carbonate, but currently the agent A-1 and the agent A-2 are combined to form a two pack type consisting of the agent A and the agent B, said two pack type being the mainstream.
Today, the bicarbonate dialysis agent is formulated so as to have the following composition and concentration when clinically used as a dialysate.
TABLE 1Na+:130 to 150mEq/LK+:0 to 3.0mEq/LCa2+:2.0 to 4.0mEq/LMg2+:0 to 2.0mEq/LCl−:90 to 120mEq/LHCO3−:20 to 40mEq/LAcetic acid:0 to 12mEq/LCitric acid:0 to 3mEq/LGlucose:0 to 250mg/dL
The dialysate at the time of dialysis treatment is used by diluting and mixing a liquid type agent A, or the agent A obtained by dissolving a powder type agent A, or the agent A obtained by dissolving a powder type agent A-1 or A-2, with a liquid type agent B, or the agent B obtained by dissolving a powder type agent B. However, as mentioned above, carbon dioxide gas is generated as a result of coexistence of an acid and sodium hydrogen carbonate over time and the pH rises at the same time, so that an insoluble calcium carbonate and the like may be generated. By this phenomenon, there has been raised such a problem that calcium concentration effective in the treatment is reduced and crystals are adhered to the tube or hose of the dialysis device.
On the other hand, acetic acid has been used for a long time as a pH adjusting agent, but, in recent years, peripheral vasodilator action and cardiac inhibitory effect, induction of inflammatory cytokines, and burden on the patient with acetate intolerance, due to acetic acid have been questioned. That is, because acetic acid is metabolized in a short time, it is not accumulated in the living body, but it has a cardiac inhibitory effect, a peripheral vasodilator action, and, as a result, an action of reducing blood pressure. Because dialysis treatment is also a treatment for the removal of moisture in the body, a reduction in blood pressure due to moisture removal during dialysis and after dialysis would inevitably occur. The symptomatic treatment such as control of moisture removal and administration of vasopressors is often used in combination to prevent the reduction in blood pressure. The presence or absence of symptoms caused by these effects are different for each patient, and thus it is thought that such symptoms may also be attributed to the concentration of acetic acid contained in the dialysate. In recent years, a dialysis method without acetic acid (an acetate free dialysis method) as one approach to overcome such a situation has been proposed.
Therefore, nowadays, those obtained by formulating citric acid in place of acetic acid as a pH adjusting agent are commercially available and have been clinically used (for example, see JP 2003-104869 A, WO 2005/094918, JP H10-087478 A and WO 2010/112570). However, there has been raised such a problem that because citric acid has a strong chelating action, a portion of the calcium in the dialysate is chelated, thereby to decrease the ionized calcium concentration, and because citric acid is a stronger acid than acetic acid, the pH of the concentrated solution A becomes lower to cause a risk of corrosion of parts of a dialysate delivery system or a dialysis machine. On the contrary, if a large amount of organic acid salts are formulated in order to increase the pH of the solution A, crystals of calcium citrate are precipitated to affect the composition, and this is also a problem. In other words, because citric acid is easy to form a chelate with an alkaline earth metal, it forms a chelate with calcium and magnesium in the dialysate component. This effect is stronger for calcium in particular, and since control of the amount of calcium is very important in dialysis treatment, there is a drawback such that decrease of ionized calcium concentration due to such a chelate significantly affects the calcium balance in patients. For example, if the calcium and citric acid were included at almost the same concentration (ion equivalent ratio) in the dialysate, about 35% of calcium is chelated to reduce the ionized calcium concentration in the dialysate by a corresponding amount, resulting in a difficulty to control the blood calcium level. In addition, since citric acid also enters the body by dialysis, there is a risk such that citric acid binds to calcium in the blood to generate a poorly soluble calcium citrate, which is then deposited in the blood vessel. In addition, there is a concern such that it becomes difficult to control the calcium important in the living body in dialysis patients because there is no explicit dynamics of the components such as citric acid and calcium after they entered the blood at the same time. Furthermore, there is a problem in the following points in that the decrease in ionized calcium concentration due to citric acid promotes the relaxation of cardiac muscle and vascular smooth muscle, leading to low blood pressure, and that citric acid is difficult to use in patients with bleeding tendency because it has an anticoagulant effect.
Further, citric acid is easy to handle in the normal handling because it is a solid, but since its concentrate is strongly acidic, hydrogen chloride gas is easily generated upon partial moisture absorption even if it is stored in powder form, which may cause a partial metal corrosion of the dialysate delivery system, resin deterioration, and the like. For example, JP 2003-104869 A describes a powder-type dialysis agent free from acetic acid, said dialysis agent being able to prevent the formation of insoluble compounds, suppress the precipitation of calcium carbonate, and inhibit the degradation of glucose by using a citric acid. These effects can be achieved by using citric acid within a limited range of pH 2.2 to 2.9. There is a problem such that there is a risk of corrosion of the dialysate delivery system and the dialysis machine within such a pH range and the decrease in the ionized calcium concentration due to the strong chelation effect of citric acid may also affect the therapeutic effect as described above.
Therefore, it is not optimal to use citric acid as an acid other than acetic acid and it is considered to use safe substances to the living body, such as an organic acid other than citric acid, including lactic acid, malic acid, fumaric acid, gluconic acid, etc., but it is also important to reduce the amount of these acids as much as possible because it is not clear about their behavior in the body after dialysis in chronic use and to take into account the influence of these acid components on the dialysate delivery system and the dialysis machine.
On the other hand, as described above, citric acid etc. would decrease the ionized calcium concentration due to its strong chelating action is concerned, but, strictly speaking, acetic acid also reduces the ionized calcium concentration. The clinical problem of acetic acid has been neglected because of its probable faster metabolism, but, in practice, the ionized calcium concentration when formed into a dialysate using acetic acid becomes lower than that of a dialysate using hydrochloric acid as the pH adjusting agent, and the ionized calcium concentration is further reduced as the content of acetic acid is increased. Although not known in general, it is certain that a large content of acetic acid becomes a factor in lowering the ionized calcium concentration, but not as much as citric acid, in the dialysis. From this point, it is clear that a less content of acetic acid is desirable.
The dialysis agent A containing acetic acid, which has been sold in Japan in the past, has a total acetic acid content of 8 mEq/L or more and a ratio of 1:2.2 or more of acetic acid:sodium acetate regardless of a liquid or a solid. The dialysis agent A having the ratio less than the above has not been used. Since the pH of the liquid A is 4.6 or more under this condition, there is such an advantage that the dialysate delivery system is less likely to be corroded and easy to handle, when viewed from the aspect of production of the liquid formulation.
The reason of the formulation of 8 mEq/L or more of the total acetate content in Japan is because benefits of bicarbonate and benefits of acetate, i.e., benefits to correct blood bicarbonate ions directly and benefits to correct bicarbonate ions slowly through the acetate metabolism are combined so as to obtain a dual formulation when changed to the bicarbonate dialysis agent from the past acetate dialysis agent (sodium acetate is formulated in 30 mEq/L or more without using sodium bicarbonate).
On the other hand, liquid preparations (liquid A) are sold primarily outside of Japan. Since in Japan, sodium acetate is used as a part of the alkalizing agent, but only sodium bicarbonate as the agent B is used as the alkalizing agent outside of Japan, sodium acetate has not been used. Therefore, as an acetate component, only acetic acid in an amount of 4 mEq/L or less has been used mainly as a pH adjusting agent.
However, when sodium acetate is not included as described above, the pH of liquid A becomes 3 or less, resulting in adverse effects such as corrosion of the metal member of the dialysate delivery system and the dialysis machine, and strong irritation to the skin. In late years, a liquid A (including those that were prepared by dissolving an agent A powder) having a pH of 3 or less has been commercially available and the dialysate preparation equipment manufacturers also deal with such a liquid A by employing acid resistant materials strongly resistant to corrosion as a component material. However, these materials are economically unfavorable because they are expensive.
In addition, the dialysate containing acetic acid in the dialysis facilities where large quantities of acetic acid are handled even though it is a liquid, and acetic acid odor is very strong and uncomfortable, because of which it also becomes necessary to care the dialysis agent not to be placed in an open system as much as possible during its manufacturing or handling.
Next, in Japan, powder preparations of dialysis agents become the mainstream from the flow of powdering, and a number of patents relating to bicarbonate dialysis agents corresponding to such powdering have been disclosed. For example, JP H07-24061 A describes that the manufacturing of the powder preparation becomes easier, when sodium acetate is combined to acetic acid in a ratio (molar ratio) of 1.56 to 3.29, preferably 2.49 to 3.29, in a powdery dialysis agent A because sodium acetate easily adsorbs acetic acid and is difficult to volatilize. However, even in the technique disclosed by JP H07-24061 A, the total acetate ion content of the finally prepared dialysate is assumed to be 8 mEq/L or more.
In addition, it is typical that sodium acetate is combined in an amount of from more than two times to five times, relative to acetic acid, and, for example, combination ratio of sodium acetate is 2.2 times (acetic acid 2.5 mEq/L:sodium acetate 5.5 mEq/L) for commercially available LYMPACK TA-1 in Japan, three times (acetic acid 2 mEq/L:sodium acetate 6 mEq/L) for KINDALY 2E, 4.5 times (acetic acid 2 mEq/L:sodium acetate 9 mEq/L) for HYSORB-F, and 5 times (acetic acid 2 mEq/L:sodium acetate 10 mEq/L) for HYSORB-D. Even apart from the transition of formulation in the past, the reason why the ratio of two times or less of sodium acetate to acetic acid has not yet been disclosed is because there was a problem with acetic acid odor. In other words, as the ratio of sodium acetate is increased to three times and four times, the acetic acid odor in powder preparation is reduced. On the contrary, the ratio of sodium acetate relative to acetic acid becomes close to double or becomes double or less, an excruciating acetic acid odor occurs, because of which its practical use is not possible.
As seen from the above, even in Japan and abroad, there remains use of a dialysate using acetic acid and having a total acetate ion content of 4 mEq/L or less, or 8 mEq/L or more, and there has been no dialysis agent put to practical use, wherein the pH of the liquid A (concentrate) obtained by dissolving a solid agent A in water is set to about 4 and the total acetate ion content in the dialysate is set to 4 to 8 mEq/L.
Only JP H06-245995 A discloses that a preferable total acetate ion content is up to 5 mEq/L in the dialysate using acetic acid and sodium acetate. However, JP H06-245995 A discloses a primary concentrate (sodium hydrogen carbonate, sodium chloride, and sodium acetate) and an individual concentrate (sodium, potassium, calcium, magnesium, hydrochloric acid/or acetic acid, glucose), and describes that the molar ratio of acetate/sodium in the final dialysate obtained by combining the primary concentrate with the individual concentrate is 0.03 or less. That is, if the sodium content in the dialysate is typically set to 140 mEq/L, the total content of acetate ions in the dialysate corresponds to 4.2 mEq/L or less. Further, the sodium acetate to be combined with the primary concentrate is in an acetate/sodium ratio of less than 0.03, and this indicates that the acetate ion content in the dialysate is less than about 4 mEq/L. That is, JP H06-245995 A discloses the embodiment of only a dialysis agent useful in the production of a dialysate having a total acetate ion content of less than about 4 mEq/L.
In addition, the dialysis agent of JP H06-245995 A enables individual patients to select various individual concentrates that can be provided, and the object of combining sodium acetate is to improve the stability and preserving property of the primary concentrate at low temperatures. In other words, a small amount of sodium acetate in the primary concentrate increases the solubility of sodium hydrogen carbonate and suppresses the formation of precipitates.
That is, since the dialysis agent of JP H06-245995 A enables to perform the dialysis with various formulations according to the individual patients (calcium, magnesium, potassium, etc.) and requires a fairly complex system so that acetic acid and acetate salt are designed to be combined into different preparations respectively, it differs from a two pack type dialysis agent comprising generally agent A and agent B in its dosage form and preparation method of the dialysate. In addition, the technical means for reducing the acetic acid odor in the dialysis agent has not been studied at all in JP H06-245995 A. Further, in the dialysis agent of JP H06-245995 A, since the individual concentrate includes hydrochloric acid or acetic acid and does not include a basic component, so that it will be exposed to a strong acidic condition of pH 3 or less, it cannot be said that the dialysis agent of JP H06-245995 A is not necessarily a good preparation in regard to corrosion problems of the dialysate delivery system, stability of glucose, and the like.
As described above, in combination of the agent A (electrolytes, acids, glucose, etc.) and the agent B (sodium hydrogen carbonate) that is widely used as a general two pack type dialysis agent, a dialysis agent having a total acetate ion content of 4 to 8 mEq/L does not exist, let alone there was no dialysis agent in powder form for practical use due to its strong acetic acid odor.
In fact, domestically and abroad, there is no successful example of any actual commercialization of dialysis agents in powder form, wherein the total acetate ion content has been set to less than 8 mEq/L in the dialysate. This is probably because commercialization capable of withstanding clinical use in terms of fluidity and stability, and acetic acid odor as a dialysis agent in powder form is difficult. For example, acetic acid has a big influence on environment in the point with its pungent odor. Clinical dialysate preparation is generally performed by a clinical engineer, but there is a problem at the point of discomfort associated with pungent odor that is generated. Furthermore, because acetic acid also becomes the degradation factor of glucose, a formulation design with sufficient consideration of stability of glucose is required for a dialysis agent using acetic acid and containing glucose. Therefore, it is necessary to find the optimal formulation while sufficiently considering such problems.
In recent years, it has been reported at conferences and the like that a lower content of total acetate ions in the dialysate is physiologically desirable and the total acetate ions are preferably less than 6 mEq/L or less than 4 mEq/L. Thus, development of a dialysis agent that can be set to a lower total acetate ion content has been more and more strongly demanded. By suppressing the total acetate ion content within a low range in this way, it is believed that the onset of symptoms such as decrease in blood pressure can be suppressed without almost raising blood acetic acid concentration of the patient during dialysis, thereby to significantly improve safety, because the metabolic rate of acetic acid is faster than that of other organic acids and the content of acetic acid is less than that of conventional products.
Based on the background of such a prior art, the development of a dialysis agent that is able to set the total acetate ion content in the dialysate to a low value, is excellent in storage stability of glucose or the like, can reduce the acetic acid odor and suppress the corrosion of the dialysate delivery system and the dialysis machine, and can be put into practical use, has been desired.